SUMMARY. The US is in the midst of an unprecedented pain management crisis. Low back pain (LBP) is the most common chronic pain condition in adults and the leading cause of disability worldwide. Guidelines have recommended non-pharmacologic treatments like spinal manipulation and behavioral approaches for LBP for nearly a decade, however uptake in practice has been poor. Little is known about the role of these treatments in secondary prevention of chronic LBP (cLBP), especially for patients with biopsychosocial risk factors. With burgeoning costs of cLBP and mounting evidence of ineffectiveness and harms of commonly used drug treatments, including opioids, there is a critical need for research on non-pharmacological treatments for cLBP prevention that can be readily translated to practice. The long-term objective is to reduce overall LBP burden by testing scalable first-line non-pharmacologic strategies that address the biopsychosocial aspects of acute/sub-acute LBP and prevent transition to cLBP. We propose a novel randomized hybrid trial addressing both effectiveness and implementation. A total of 1180 patients will be enrolled with nonspecific LBP of 2-12 weeks duration, at medium and high risk of developing cLBP using the Subgroups for Targeted Treatment (STarT) Back Screening Tool (SBST). Aim 1 will assess the effectiveness of Spinal Manipulation Therapy (SMT), Structured Self-Management (SSM), and SMT+SSM relative to Usual Medical Care (UMC) in a randomized trial using a 2x2 factorial design. Primary outcomes are prevention of cLBP at 12 months; recovery from acute/sub-acute LBP at 6 months; and cumulative reduction of pain and disability over 1 year. Secondary outcomes include PROMIS-29, productivity loss, health care use, and medication use (including opioids). Aim 2: will use mixed methods to gather data about important influences on the interventions that could affect results interpretation and future implementation. Aligned with the National Center for Complementary and Integrative Health's (NCCIH) Strategic Plan 2016, this project has the potential to significantly transform LBP management by providing definitive and generalizable evidence regarding front-line non-pharmacologic interventions addressing physical and psychosocial factors for the prevention of cLBP. By empowering patients to engage in healthy pain management behaviors, we anticipate LBP related disability, productivity loss, and reliance on continued health care and medication use (including opioids) will be reduced. The comprehensive dissemination and implementation strategy, informed by major stakeholders, will facilitate translation into clinical practice across health professions.